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Oral Controlled Release Dosage Form - Patent 7988993

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United States Patent: 7988993


































 
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	United States Patent 
	7,988,993



 Dixit
,   et al.

 
August 2, 2011




Oral controlled release dosage form



Abstract

 A dosage form that provides a controlled release solid dosage form for
     the oral administration of a central nervous system stimulant, preferably
     methylphenidate hydrochloride.


 
Inventors: 
 Dixit; Manesh (Sunrise, FL), Chen; Chih-Ming (Taipei, TW), Cheng; Xiu Xiu (Weston, FL), Xie; Jianbo (Davie, FL) 
 Assignee:


Andrx Pharmaceuticals, Inc.
 (Davie, 
FL)





Appl. No.:
                    
10/726,024
  
Filed:
                      
  December 2, 2003

 Related U.S. Patent Documents   
 

Application NumberFiling DatePatent NumberIssue Date
 60431954Dec., 2002
 

 



  
Current U.S. Class:
  424/452  ; 424/463
  
Current International Class: 
  A61K 9/48&nbsp(20060101); A61K 9/26&nbsp(20060101)
  
Field of Search: 
  
  

 424/469,452
  

References Cited  [Referenced By]
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4519801
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Edgren

4612008
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4783337
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4874613
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Hsiao

4894240
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4952402
August 1990
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5023088
June 1991
Wong et al.

5082668
January 1992
Wong et al.

5654005
August 1997
Chen et al.

5773478
June 1998
Richards et al.

5837284
November 1998
Mehta et al.

5874090
February 1999
Baker et al.

5908850
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5914129
June 1999
Mauskop

6228398
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Devane et al.

6312728
November 2001
Beiman et al.

6322819
November 2001
Burnside et al.

6340476
January 2002
Midha et al.

6344215
February 2002
Bettman et al.

6355656
March 2002
Zeitlin et al.

6368626
April 2002
Bhatt et al.

6372254
April 2002
Ting et al.

6417184
July 2002
Ockert

6419952
July 2002
Wong et al.

6419960
July 2002
Krishnamurthy et al.

6475493
November 2002
Mulye

6495154
December 2002
Tam et al.

6500459
December 2002
Chhabra et al.

6503950
January 2003
Ockert

6531489
March 2003
Harris et al.

6555127
April 2003
Steiner

6555136
April 2003
Midha

6602521
August 2003
Ting et al.

6627223
September 2003
Percel et al.

6635284
October 2003
Mehta et al.

6638533
October 2003
Krsek

6673367
January 2004
Goldenheim et al.

6692767
February 2004
Burnside et al.



 Foreign Patent Documents
 
 
 
0 320 097
Jun., 1989
EP

WO 98/06380
Feb., 1998
WO

WO 98/14168
Apr., 1998
WO

WO 98/23263
Jun., 1998
WO

WO 99/03471
Jan., 1999
WO

WO 99/62496
Dec., 1999
WO

WO 00/35450
Jun., 2000
WO



   Primary Examiner: Padmanabhan; Sreeni


  Assistant Examiner: Claytor; Renee


  Attorney, Agent or Firm: Florek & Endres PLLC



Parent Case Text



 The present application claims priority to U.S. Provisional Patent No.
     60/431,954, filed Dec. 9, 2002.

Claims  

We claim:

 1.  A controlled release methylphenidate tablet consisting of: (A) an immediate release methylphenidate coating consisting of;  (a) 30-60 weight percent based upon the total weight of
the immediate release coating of methylphenidate or a pharmaceutically acceptable salt or isomer thereof;  (b) 40-70 weight percent based upon the total weight of the immediate release coating of a binder;  and (c) 0.005-5 weight percent based upon the
total weight of the immediate release coating of a stabilizer;  (B) a controlled release methylphenidate core tablet consisting of: (a) a compressed mixture consisting of: (i) 5-40 weight percent based upon the total weight of the compressed mixture of
methylphenidate or a pharmaceutically acceptable salt or isomer thereof;  (ii) 3-40 weight percent based upon the total weight of the compressed mixture of a hydrogel polymer;  (iii) 25-90 weight percent based upon the total weight of the compressed
mixture of a diluent;  and (iv) optionally a lubricant;  and (b) an enteric coating surrounding the core tablet consisting essentially of;  (i) 45-80 weight percent based upon the total weight of the enteric coating of a combination of enteric polymers
consisting of zein and at least one additional enteric polymer selected from the group consisting of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate,
cellulose acetate trimellitate, shellac, polyvinyl acetate phthalate or mixtures thereof;  (ii) 0.5-15 weight percent based upon the total weight of the enteric coating of a plasticizer;  (iii) an anti-sticking agent;  and (iv) a surfactant;  and (C)
optionally an aesthetic coating;  wherein the controlled release methylphenidate tablet exhibits the following dissolution profile when tested in a United States Pharmacopeia type 2 (paddle) apparatus at 50 rpms in 900 ml of phosphate buffer with a pH of
7.5 and at 37.degree.  C.: 1-35% of the methylphenidate is released after 1 hour;  5-40% of the methylphenidate is released after 2 hours;  and not less than 70% is release after 10 hours;  and when administered to humans exhibits a plasma peak for the
immediate release layer (T.sub.max1) between 1 and 5 hours, a plasma peak for the controlled release core (T.sub.max2) between 4 and 12 hours, and a plasma trough (T.sub.min) between 2 and 7 hours in between the two peak plasma levels;  and wherein the
immediate release methylphenidate coating (A) is applied to the enteric coating surrounding the core tablet.


 2.  The controlled release methylphenidate tablet as defined in claim 1 wherein: (A) the immediate release methylphenidate coating consists of;  (a) 40-50 weight percent based upon the total weight of the immediate release coating of
methylphenidate or a pharmaceutically acceptable salt or isomer thereof;  (b) 45-60 weight percent based upon the total weight of the immediate release coating of a binder;  and (c) 0.01-2 weight percent based upon the total weight of the immediate
release coating of a stabilizer;  (B) the controlled release methylphenidate core tablet consists of: (a) a compressed mixture consisting of: (i) 10-25 weight percent based upon the total weight of the compressed mixture of methylphenidate or a
pharmaceutically acceptable salt or isomer thereof;  (ii) 3-40 weight percent based upon the total weight of the compressed mixture of a hydrogel polymer;  (iii) 45-85 weight percent based upon the total weight of the compressed mixture of a diluent; 
and (iv) 0.1-10 weight percent based upon the total weight of the compressed mixture of a lubricant;  and (b) an enteric coating surrounding the core tablet consisting of;  (i) 45-80 weight percent based upon the total weight of the enteric coating of
the combination of enteric polymers;  (ii) 1-5 weight percent based upon the total weight of the enteric coating of a plasticizer;  (iii) an anti-sticking agent;  and (iv) optionally a surfactant.


 3.  The controlled release tablet of claim 1 wherein the at least one additional enteric polymer is a methacrylic acid copolymer.


 4.  The controlled release methylphenidate tablet as defined in claim 3 wherein the T.sub.max2 occurs about 7 to 9 hours and declines to about 1.4 ng/ml in about 14 to 18 hours.


 5.  The controlled release methylphenidate tablet of claim 2 wherein the compressed mixture of the core tablet consists of 0.5-5 weight percent based upon the total weight of the compressed mixture of a lubricant. 
Description  

BACKGROUND OF THE INVENTION


 1.  Field of the Invention


 The present invention relates to the improved dosing of medication.  Specifically, this invention improves the therapeutic effect of a central nervous system stimulant such as methylphenidate hydrochloride by delivering the medication over a
predetermined period of time.  In the present invention an initial immediate dose of the central nervous system stimulant is delivered followed by a second controlled dose of the medication from a single oral dosage form.  The invention helps improve
patient compliance and decreases the need for additional daily doses of the medication.


 2.  Description of the Related Art


 Methylphenidate is a central nervous system stimulant used to treat Attention-Deficit Disorder (ADD) and Attention-Deficit Hyperactivity Disorder (ADHD), available commercially as, e.g. RITALIN SR.RTM., CONCERTA.TM., METADATE.TM.  CD capsules
and METEADATE.TM.  ER Tablets.  The beneficial results seen by clinicians in the treatment of ADD and ADHD has resulted in widespread use of methylphenidate in more than two million patients annually.  Methylphenidate exists in four separate optical
isomers, 1-threo, d-erythro, d-threo and 1-erythro, with the threo pair of enantiomers (racemate) of methylphenidate hydrochloride generally administered for the treatment of ADD and ADHD.  Methylphenidate hydrochloride is a mild central nervous system
stimulant with pharmacological properties similar to that of amphetamines.  The side effects which are associated with the use of methylphenidate include anorexia, weight loss, insomnia, dizziness and dysphoria.  Methylphenidate is categorized by the DEA
as a Schedule II controlled substance because it produces a euphoric effect when administered intravenously or through inhalation or ingestion, and thus carries a high potential for abuse.


 Numerous sustained release formulations of methylphenidate which provide for a slow release of the medication over a predetermined period of time have been developed and some of these formulations are described in U.S.  Pat.  Nos.  6,340,476,
6,344,215, 6,372,254, 6,368,626, 5,837,284 and 6,034,101, incorporated herein by reference.  However, when methylphenidate is delivered at a steady state over a sustained period of time, acute tolerance often develops.  The undesirable clinical effects
of steady state sustained release formulations are overcome by multiple dosing whereby the intensity of the therapeutic effects of the methylphenidate can be maintained.


 The sustained release tablet form of methylphenidate hydrochloride described in U.S.  Pat.  No. 6,034,101 and incorporated herein by reference, comprises a sustained release tablet that provides an ascending dose of the drug.  This does not
model the multiple dose administration of immediate release methylphenidate hydrochloride tablets.  Controlled release of the medication is achieved by a hydrogel matrix.


 The sustained release formulation of methylphenidate described in U.S.  Pat.  No. 5,837,284 and incorporated herein by reference, is made up of two groups of particles.  One group provides a substantially immediate dose of methylphenidate drug,
the other supplies a dose of methylphenidate delayed by about 2 to 7 hours.


 Sustained release formulations of methylphenidate have been developed, which provide for the slow release of the drug over the course of the day.  However it has been observed that peak plasma concentrations of the drug are lower when sustained
release formulations are used.  Studies have shown that sustained release formulations of methylphenidate have been shown to have lower efficacy than conventional dosage forms.


 Although the prior art controlled release formulation provide steady increases in the blood level of methylphenidate hydrochloride, they may be less than desirable because their delivery rates do not mimic the plasma profile of multiple dose
regimens known to prevent tolerance.


 To overcome the previously mentioned problems with sustained delivery of methylphenidate, the present invention provides the needed delivery system whereby the drug can be administered in a single dose and provide the needed delivery rate so
that tolerance to its effects will not develop.  Furthermore, a single effective daily dose will eliminate the risk of theft or loss of the second dose and increase the medications overall therapeutic value.


SUMMARY OF THE INVENTION


 The present invention is a novel unitary dosage formulation of a central nervous system stimulant which provides for an enhanced dosage delivery efficiency which effectively reproduces the effects of multiple dose therapy.  The active ingredient
is delivered such that plasma peaks and troughs experienced in multiple dosing are present.  Thus, the invention provides a single dose delivery system that attains the desired therapeutic multiple dosing regimen plasma levels.


 One embodiment of the present invention provides a unitary controlled release solid dosage form for the oral administration of a central nervous system stimulant such as methylphenidate hydrochloride.  The pharmaceutical formulation contains a
drug core or tablet, a controlled release coating surrounding the core or tablet, an immediate release layer applied to the controlled release coating and an optionally aesthetic overcoat covering.  The core tablet is a mixture of the active
pharmaceutical compound, a diluent, a binding agent and optionally other conventional processing aids such as anti-sticking agents, fillers and glidants.  The controlled release coating surrounds the core tablet and is comprised of an enteric polymer and
optionally other conventional processing aids such as surfactants, plasticizers and anti-sticking agents.  The immediate release drug layer is applied over the controlled release coating and is a mixture of active ingredient, a binder, and an optionally
a stabilizer.  An overcoat or aesthetic coating may be applied to the final dosage form.


 In a preferred embodiment, the present invention is a controlled release pharmaceutical dosage formulation for oral administration comprising a core with a central nervous system stimulant, an enteric polymer surrounding the core and an
immediate release layer comprising a central nervous system stimulant and a stabilizer, wherein the formulation when administered to humans exhibits one of the following characteristics: (a) a maximum plasma concentration up to about 20 ng/ml,
preferably, a maximum plasma concentration of about 3 to about 20 ng/ml; (b) an AUC.sub.0-24 up to about 200 ng/ml, preferably, an AUC.sub.0-24 of about 30 to about 200 (ng hr)/ml; (c) a T.sub.max of about 3 to about 12 hours; or any combination of the
foregoing.


 In a preferred embodiment, the present invention is a controlled release pharmaceutical dosage formulation for oral administration comprising a core with a central nervous system stimulant, an enteric polymer surrounding the core and an
immediate release layer comprising a central nervous system stimulant and a stabilizer.  Wherein, the active ingredient when administered to humans is characterized by a plasma peak for the immediate release layer (T.sub.max1) between 1 and 5 hours, a
plasma peak for the controlled release core (T.sub.max2) between 4 and 12 hours, and a plasma trough (T.sub.min) between 2 and 7 hours in between the two peak plasma levels.


 Other objects, features and advantages of the invention are not taught in the prior art but will be more apparent to those versed in the art from the following specifications, taken in conjunction with the accompanying claims. 

BRIEF
DESCRIPTIONS OF DRAWINGS


 FIG. 1 is a graph depicting mean plasma concentration, under fasting conditions, of a single controlled release dose of methylphenidate hydrochloride from the formulation as described in Example 1 in ng/ml over a 24 hour period of the verses the
mean Plasma concentration of an equivalent dose of the commercially available controlled release form of methylphenidate (CONCERTA.TM.).


 FIG. 2 is a graph depicting the dissolution profile over a 24 hour period in water-1% pepsin for the formulation as described in Example 1.


 FIG. 3 is a graph depicting mean plasma concentration, under fasting conditions, of a single controlled release dose of methylphenidate hydrochloride from the formulation as described in Example 2 in ng/ml over a 24 hour period of the verses the
mean Plasma concentration of an equivalent dose of the commercially available controlled release form of methylphenidate (CONCERTA.TM.).


 FIG. 4 is a graph depicting the dissolution profile of a preferred embodiment of the present invention.  The graph shows the dissolution for 36 mg methylphenidate HCl controlled release tablets as described in Batch 1 of Example 3 over a 10 hour
period.


 FIG. 5 is a graph depicting the dissolution profiles of a preferred embodiment of the present invention.  The graph shows the dissolution for 36 mg methylphenidate HCl controlled release tablets as described in Batch 2 of Example 3 over a 10
hour period.


 FIG. 6 is a graph depicting the dissolution profile in a pH 7.5 phosphate buffer solution of the formulation as described in Example 4.


DETAILED DESCRIPTION OF THE INVENTION


 The invention provides a controlled release formulation of a central nervous system stimulant, preferably methylphenidate and its pharmaceutically acceptable salts, for oral administration, said formulation comprising: (1) a core comprising: (a)
central nervous system stimulant such as methylphenidate and its pharmaceutically acceptable salts, isomers or pharmaceutically acceptable mixture thereof; (b) a binding agent; (c) a diluent; and (2) a controlled release coating surrounding the core
comprising; (a) an enteric polymer; (b) a plasticizer; and (c) optionally a anti-sticking agent; and (3) an immediate release drug layer comprising; (a) a central nervous system stimulant, preferably methylphenidate and its pharmaceutically acceptable
salts, isomers or pharmaceutically acceptable mixture thereof; (b) a binder; and (c) optionally a stabilizer; and (4) optionally an overcoat comprising; (a) a coating agent.


 The core of the present invention comprises about 1-50% based on the total weight of the core of a central nervous system stimulant and preferably 5-40% and most preferably 10-25% of the total weight of the core.


 The core should also comprise a binding agent.  The binding agent can be any type of material commonly known in the pharmaceutical art.  Acceptable binder materials can be polymeric, non-polymer, water soluble or water insoluble.  Preferably,
the binding agent employed in the core is water soluble, gels or swells (hydrogel forming polymer) in the presence of water.  Some of the commonly known binders are acacia, alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin,
ethylcellulose, gelatin, liquid glucose, polyvinyl pyrrolidone, carboxyvinyl polymer, methylcellulose, hydroxymethyl cellulose, low molecular weight polyethylene oxide polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose (HPMC), gums, acrylate polymers, methacrylate polymers, maltodextrin and mixtures of the foregoing.  The preferred binder for use in the core is hydroxypropylmethyl cellulose, such as the material sold as Methocele.TM.  K-100M.  The
amount of binder in the core should comprise 1 to about 50% of the total weight of the core and preferably about 3 to about 40% of the total weight of the core.


 The core may optionally contain a diluent or filler.  If a diluent or filler is employed in the core, it can be any type of diluent commonly known in the art such as sugars, starches or vegetable oils.  Examples of some preferred diluent are
lactose monohydrate, calcium carbonate, calcium sulfate, microcrystalline cellulose, calcium phosphate, dextrin, dextrose, maltitol, maltose, starch, sucrose or talc.  In a preferred embodiment of the present invention, the diluent used in the core of
the tablet is lactose monohydrate.  If a diluent is used in the core, the amount should be about 1% to about 95% based on the total weight of the core, preferably 25% to 90% based on the total weight of the core, and most preferably about 40% to about
85% based on the total weight of the core.


 The core may also optionally contain a lubricant agent.  Lubricant agents are used to facilitate manufacturing of the formulation, some examples of suitable anti-sticking agents include, talc, glyceryl monostearates, calcium stearate, magnesium
stearate, stearic acid, glyceryl behenate, and polyethylene glycol, and are preferably present at no more than approximately about 0.05 to about 15% based upon the total weight of the core, preferably about 0.1 to about 10% based upon the total weight of
the core and most preferably about 0.5 to about 5% based upon the total weight of the core.


 The core of the present invention is preferably formed by mixing the core ingredients and tableting the mixture using techniques commonly known in the art.  The core may also be formed by granulating the core ingredients and compressing the
granules with or without the addition of an anti-sticking agent into a tablet.


 In a preferred embodiment the core is subsequently coated with a controlled release coating.  This controlled release coating is applied by conventional coating techniques, such as pan coating or fluid bed coating using solution, suspension or
dispersion of polymeric material in water or suitable organic solvents.  A particularly preferred controlled release coating employs an enteric polymer.  The controlled release coating comprises about 2 to about 50 weight percent of the coated core,
preferably about 5 to about 30 weight percent of the coated core.  Preferably, the enteric polymer employed in the controlled release coating is selected from the group consisting of zein, methacrylic acid copolymers, cellulose acetate phthalate,
hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac, polyvinyl acetate phthalate or mixtures thereof.  The amount of enteric polymer material in the controlled release coating
is preferably about 5 to about 95 weight percent, preferably about 10 to about 70 weight percent based on the total weight of the controlled release coating.  In one embodiment of the invention the amount of enteric polymer material in the controlled
release coating is 45 to 80 weight percent based on the total weight of the controlled release coating.  In a preferred embodiment of the present invention, a mixture of zein and methacrylic acid copolymer is employed.  The methacrylic acid copolymer is
selected from the group of enteric polymers, preferably Eudragit S. The preferred ratio of zein to methacrylic acid copolymer is 1:5 to 5:1 with the most preferred ratio being 2:1 to 4:1.


 The controlled release coating also preferably contains plasticizers.  Plasticizers which may be used include any of those known to those skilled in the art, including but not limited to, acetyltributyl citrate, triacetin, acetylated
monoglyceride, rape oil, olive oil, sesame oil, coconut oil, poloxamer, acetyltriethyl citrate, glycerin, sorbitol, diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylphthalate, dibutylsebacate,
triethyl citrate, tributylcitrate, glyceroltributyrate, polyethylene glycol, propylene glycol and mixtures thereof.  The preferred plasticizer is acetyltributyl citrate.  The amount of plasticizer employed in the controlled release coating can range from
about 0.1 to about 30%, preferably about 0.5 to about 15% and most preferably about 1 to about 5% based on the total weight of the controlled release coating.


 The controlled release coating may also include an anti-sticking agent such as those selected from the group consisting of talc, colloidal silica dioxide, magnesium stearate, magnesium silicate, glyceryl monostearates, calcium stearate or steric
acid.  The preferred anti-sticking agent is talc.  If an anti-sticking agent is employed in the controlled release coating, the amount employed should range from about 10 to about 70 percent, and most preferably 20-60% based on the total weight of the
coating.


 In a preferred embodiment of the present invention, a second coating is applied to the controlled release coating to form an immediate release portion of the dosage formulation.  This second or immediate release layer is comprised of the
pharmaceutically central nervous system stimulant and a binder that preferably is a pharmaceutically acceptable water-soluble or rapidly dispersing material.  The binder employed can be any type of binding agent commonly known in the art such as those
described above.  In a preferred embodiment of the present invention, the binder for the immediate release coating is a water soluble polymer such as hydroxypropyl methylcellulose, commercially available under the trade name Methocel.RTM.  E-5.  A
preferred composition, the binder should comprise about 40 to about 70% of the total weight of the immediate release layer and preferably about 45 to about 60 weight percent of the total weight of the immediate release layer.


 The immediate release coating may also contain a stabilizer for the pharmaceutically active compound.  In a preferred embodiment of the present invention, a stabilizer is a material that causes the pH of the immediate release coating solution to
have a pH of about 7 or below.  The preferred stabilizer is selected from the group consisting of organic acids, inorganic acids, acid addition salts, buffers and combinations thereof.  The most preferred stabilizers are organic acids such as fumaric
acid.  The preferred concentration of the stabilizer is about 0.001 to about 10%, preferably about 0.005 to about 5% and most preferably about 0.01 to about 2% based upon the total weight of the immediate release coating.


 Finally, the immediate release coating may be coated with an overcoat, polishing coat or color coat using any of the methods commonly known in the industry.


 The dissolution profile of the dosage form prepared according to the present invention is pH dependent and should exhibit the following dissolution profile when tested in a USP type 2 (paddle) apparatus at 50 rpms in 900 ml of phosphate buffer
with a of pH 7.5 and at 37.degree.  C.


 TABLE-US-00001 DRUG RELEASED Time Most (hours) Preferred Preferred 1 1-35% .sup.  5-30%.sup.  2 5-40% .sup.  10-35% 4 * NLT 25% NLT 30% 10 .sup.  NLT 70% .sup.  NLT 80% * NLT = Not Less Than


 In the preparation of the tablets of the invention, various conventional well known solvents may be used to prepare the granules and apply the external coating to the tablets of the invention.  In addition, various diluents, excipients,
anti-sticking agents dyes, pigments, dispersants etc. which are disclosed in Remington's Pharmaceutical Sciences 20.sup.th Edition, 2000, and the Handbook of Pharmaceutical Excipients, Third Edition, by Arthur H. Kibbe, which are incorporated herein by
reference, may be used to optimize the formulations of the invention.


DESCRIPTION OF THE PREFERRED EMBODIMENTS


Example 1


 A batch of once a day controlled release methylphenidate tablets in accordance with the present invention is prepared by first forming methylphenidate cores containing approximately 22 mg of methylphenidate HCl, and 14 mg methylphenidate HCl in
the immediate release layer as follows:


 (a) Core


 73.35 g of methylphenidate HCl and 396.65 g of lactose monohydrate, NF, 25.0 g of hydroxypropyl methylcellulose (Methocel K-100M Premium), 2.5 g of colloidal silicon dioxide (CAB-O-SIL) are delumped by passing the compounds through a 20 mesh
screen and then mixed with in a suitable blender for 20 minutes.  2.5 g of magnesium stearate is screened and added to the drug mixture and blended for an additional 5 minutes.  After all the ingredients are blended together, the mixture is compressed
into tablets using a rotary press fitted with 9/32'' round standard concave punches.  The target hardness is about 5 kp.


 The core tablets are then coated with a controlled release coating as follows:


 (b) Controlled Release Coating


 8.40 g of methacrylic acid copolymer (Eudragit S 100), 25.24 g of zein NF (regular Grade F4000), 2.81 g acetyltributyl citrate NF, and 33.68 g of talc USP are dispersed in 312.53 g of isopropyl alcohol USP and 56.77 g of purified water (USP)
while stirring with a homogenizer.  An additional 28.10 g of isopropyl alcohol is used to rinse the homogenizer and other equipment.  The rinse isopropyl alcohol is added to the coating suspension.  The coating suspension is then sprayed onto the tablets
in a fluidized bed coater employing the following conditions: exhaust temperature of 25-35.degree.  C.; atomization pressure of approximately 1 bar; and a spray rate of 2-6 ml/min.


 Once the controlled release coating suspension has been applied to the core tablets, the controlled release coated tablets are transferred from the fluidized bed coater onto drying trays and placed in an oven at 55-65.degree.  C. for
approximately 16 hours to allow curing of the coating.  Once the controlled release coated tablets are cured, an immediate release methylphenidate HCl coating is applied to the controlled release coated tablets as follows:


 (c) Immediate Release Coat


 19.202 g of methylphenidate hydrochloride, 19.202 g of hydroxypropyl methylcellulose (Methocel.RTM.  E5 Premium) and is dissolved in 245.636 g of purified water USP.  The mixture is rinsed with 100 g of purified water USP and then 8.951 g of
Opadry.RTM.  White YS-1-7003 is dispersed into 80.559 g of water and mixed for 1 hour.  The drug solution is sprayed onto the controlled release tablets using a fluidized bed coater employing the following conditions: exhaust temperature of 40-50.degree. C.; atomization pressure of approximately 1 bar; and a spray rate of 2-5 ml/min.


 Once the immediate release coating solution has been consumed, the Opadry.RTM.  dispersion is sprayed on the tablets.  The immediate release coated tablets are dried in the fluidized bed coater for approximately 20 minutes.  The final tablets
have approximately 14 mg of methylphenidate HCl in the immediate release coating and approximately 22 mg of methylphenidate HCl in the core.


 The resulting tablets were tested in human subjects along with CONCERTA.TM.  brand methylphenidate HCl tablets.  In a randomly assigned test the subjects were given either a single dose of 36 mg of methylphenidate controlled release formulation
described herein or an equivalent amount in a single dose of CONCERTA.TM.  brand sustained release methylphenidate HCl tablet.  The results of the in vivo testing are provided in TABLE 1 as depicted by the graph in FIG. 1.


 TABLE-US-00002 TABLE 1 Mean Plasma concentration Methylphenidate controlled release CONCERTA .TM.  2 hr 7.1 ng/ml 4.5 ng/ml 4 hr 4.7 ng/ml 5.5 ng/ml 6 hr 6.4 ng/ml 9.3 ng/ml 8 hr 7.4 ng/ml 8.4 ng/ml 12 hr 3.8 ng/ml 4.9 ng/ml 18 hr 1.1 ng/ml 1.4
ng/ml


 Dissolutions studies for drug release from the formulation of Example 1 were conducted with USP apparatus No 1, at 100 rpm in 500 ml of Water-1% Pepsin at intervals over 24 hours are as follows in TABLE 2 as depicted in graph in FIG. 2.


 TABLE-US-00003 TABLE 2 % dissolved 1 hour 37% 2 hours 37% 3.5 hours 38% 5 hours 39% 7 hours 40% 12 hours 55% 24 hours 104%


Example 2


 A batch of once a day controlled release methylphenidate tablets in accordance with the present invention is prepared by first forming methylphenidate cores containing approximately 28 mg of methylphenidate HCl, and 8 mg methylphenidate HCl in
the immediate release layer as follows:


 (a) Core


 93.35 g of methylphenidate HCl, 351.65 g of lactose monohydrate, NF, 50.0 g of hydroxypropyl methylcellulose (Methocel K-100M Premium) and 2.5 g of colloidal silicon dioxide (CAB-O-SIL) are delumped by passing the compounds through a 20 mesh
screen and then mixed in a suitable blender for 20 minutes.  2.5 g of magnesium stearate is screened and added to the drug mixture and blended for an additional 5 minutes.  After all the ingredients are blended together, the mixture is compressed into
tablets using a rotary press fitted with 9/32'' round standard concave punches.  The target hardness is about 5 kp.


 The core tablets are then coated with a controlled release coating as follows:


 (b) Controlled Release Coating


 8.40 g of methacrylic acid copolymer (Eudragit S 100), 25.24 g of zein NF (regular Grade F4000), 2.81 g acetyltributyl citrate, NF and 33.68 g of talc USP are dispersed in 312.53 g of isopropyl alcohol USP and 56.77 g of purified water (USP)
while stirring with a homogenizer.  An additional 28.10 g of isopropyl alcohol is used to rinse the homogenizer and other equipment.  The rinse isopropyl alcohol is added to the coating suspension.  The coating suspension is then sprayed onto the tablets
in a fluidized bed coater employing the following conditions: exhaust temperature of 25-35.degree.  C.; atomization pressure of approximately 1 bar; and a spray rate of 2-6 m/min.


 Once the controlled release coating suspension has been applied to a lot of core tablets, the controlled release coated tablets are transferred from the fluidized bed coater onto drying trays and placed in an oven at 55-65.degree.  C. for
approximately 16 hours to allow curing of the coating.  Once the controlled release coated tablets are cured an immediate release methylphenidate HCl coating is applied to the controlled release coated tablets as follows:


 (c) Immediate Release Coat


 10.889 g of methylphenidate hydrochloride, 10.889 g of hydroxypropyl methylcellulose (Methocel.RTM.  E5 Premium) and is dissolved in 220.261 g of purified water USP.  The mixture is rinsed with 50 g of purified water USP and then 8.251 g of
Opadry.RTM.  White YS-1-7003 is dispersed into 74.259 g of water and mixed for 1 hour.  The drug solution is sprayed onto the controlled release tablets using a fluidized bed coater employing the following conditions: exhaust temperature of 40-50.degree. C.; atomization pressure of approximately 1 bar; and a spray rate of 2-5 ml/min.


 Once the immediate release coating solution has been consumed, the Opadry.RTM.  dispersion is sprayed on the tablets.  The immediate release coated tablets are dried in the fluidized bed coater for approximately 20 minutes.  The final tablets
have approximately 8 mg of methylphenidate HCl in the immediate release coating and approximately 28 mg of methylphenidate HCl in the core.


 The resulting tablets were tested in human subjects along with CONCERTA.TM.  brand methylphenidate HCl tablets.  In a randomly assigned test the subjects were given either a single dose of 36 mg of methylphenidate controlled release formulation
described herein or an equivalent amount in a single dose of CONCERTA.TM.  brand sustained release methylphenidate HCl tablet.  The results of the in vivo testing are provided in TABLE 3 as depicted by the graph in FIG. 3.


 TABLE-US-00004 TABLE 3 Mean Plasma concentration Methylphenidate controlled release Concerta .TM.  2 hr 3.5 ng/ml 4.5 ng/ml 4 hr 3.3 ng/ml 5.5 ng/ml 6 hr 7.7 ng/ml 9.3 ng/ml 8 hr 7.9 ng/ml 8.4 ng/ml 12 hr 4.2 ng/ml 4.9 ng/ml 18 hr 1.4 ng/ml 1.4
ng/ml


Example 3


 Once a day controlled release methylphenidate tablets in accordance with the present invention are prepared by first forming methylphenidate cores containing approximately 27 mg of methylphenidate HCl, and 9 mg of methylphenidate HCl in the
immediate release layer as follows:


 (a) Core


 3.708 kg of methylphenidate HCl and 15.656 kg of lactose monohydrate, NF, 1.030 kg of hydroxypropyl methylcellulose (Methocel K-100M Premium), 0.103 kg of colloidal silicon dioxide (CAB-O-SIL) are delumped by passing the compounds through a 20
mesh screen and then mixed in an appropriate blender, then screened and blended again.  0.103 kg of magnesium stearate is screened and added to the drug mixture and blended for an additional 5 minutes.  After all the ingredients are blended together, the
mixture is compressed into tablets using a rotary press fitted with 17/64'' round standard concave punches.  The target hardness is about 6 kp.


 The core tablets are then coated with a controlled release coating as follows:


 (b) Controlled Release Coating


 0.242 kg of methacrylic acid copolymer (Eudragit S 100), 0.725 kg of zein NF (regular Grade F4000), 0.081 kg acetyltributyl citrate, NF and 0.967 kg of talc USP are dispersed in 9.000 kg of isopropyl alcohol USP and 1.631 kg of purified water
(USP) while stirring with a homogenizer.  An additional 0.787 kg of isopropyl alcohol is used to rinse the homogenizer and other equipment.  The rinse isopropyl alcohol is added to the coating suspension.  The coating suspension is then sprayed onto the
tablets in a pan coater employing the following conditions: product temperature of 30.degree.  C.; atomization pressure of approximately 20 psi; and a spray rate of approximately 30 ml/min. Remove 0.225 kg of coated tablets after spraying 11.18 kg of
dispersion corresponding to a 15% weight gain of coated tablets (Batch 1).


 Once the controlled release coating suspension has been applied to a lot of core tablets to give approximately 17.5% weight gain of coated tablets (Batch 2).  The controlled release coated tablets are transferred from the fluidized bed coater
onto drying trays and placed in an oven at 55-65.degree.  C. for approximately 16 hours to allow for curing of the coating.  Once the controlled release coated tablets are cured an immediate release methylphenidate HCl coating is applied to the
controlled release coated tablets in two batches as follows:


 (c) Immediate Release Coat


 (i) Batch 1


 In the first batch, 10.931 g of methylphenidate hydrochloride, 10.931 g of hydroxypropyl methylcellulose (Methocel.RTM.  E5 Premium) is dissolved in 211.760 g of purified water USP.  The mixture is rinsed with 46.76 g of purified water USP. 
6.862 g of Opadry.RTM.  White YS-1-7003 is dispersed into 61.760 g of water and mixed for 1 hour.  The drug solution is sprayed onto a 200 g batch of controlled release tablets having 15% coating level (Batch 1), using a fluidized bed coater employing
the following conditions: product temperature of 45.+-.5.degree.  C.; atomization pressure of 1.+-.0.5 bar; and a spray rate of 2-5 ml/min.


 Once the immediate release coating solution has been consumed, the Opadry.RTM.  dispersion is sprayed on the tablets.  The immediate release coated tablets are dried in the fluidized bed coater for approximately 20 minutes.  The final tablets
have approximately 9 mg of methylphenidate HCl in the immediate release coating and approximately 27 mg of methylphenidate HCl in the core.


 (ii) Batch 2


 In the second batch, 10.624 g of methylphenidate hydrochloride, 10.624 g of hydroxypropyl methylcellulose (Methocel.RTM.  E5 Premium) is dissolved in 211.760 g of purified water USP.  The mixture is rinsed with 41.232 g of purified water USP. 
6.843 g of Opadry.RTM.  White YS-1-7003 is dispersed into 61.760 g of water and mixed for 1 hour.  The solution is sprayed onto a 200 g batch of controlled release tablets having 17.5% coating level (Batch 2), using a fluidized bed coater employing the
following conditions: product temperature of 45.+-.5.degree.  C.; atomization pressure of 1.+-.0.5 bar; and a spray rate of 2-50 ml/min.


 Once the immediate release coating solution has been consumed, the Opadry.RTM.  dispersion is sprayed on the tablets.  The immediate release coated tablets are dried in the fluidized bed coater for approximately 20 minutes.  The final tablets
have approximately 9 mg of methylphenidate HCl in the immediate release coating and approximately 27 mg of methylphenidate HCl in the core.


 Dissolutions studies for drug release were conducted with USP apparatus No 1, at 100 rpm in 500 ml of pH 7.5 phosphate buffer (n=12) at intervals over 10 hour for the first and second batches as depicted in TABLE 4 and FIGS. 4 and 5,
respectively, are as follows:


 TABLE-US-00005 TABLE 4 First Batch Second Batch % dissolved % dissolved 1 hour 24% 23% 2 hours 26% 23% 3 hours 39% 30% 4 hours 53% 42% 6 hours 81% 67% 7 hours 95% 80% 8 hours 102% 95% 10 hours 104% 101%


Example 4


 A 50.22 kg batch of once a day controlled release methylphenidate tablets in accordance with the present invention is prepared by first forming methylphenidate cores containing approximately 40.5 mg of methylphenidate HCl, and 13.5 mg of
methylphenidate HCl in the immediate release layer as follows:


 (a) Core


 5.468 kg of methylphenidate HCl and 31.6 kg of lactose monohydrate, NF, 3.038 kg of hydroxypropyl methylcellulose (Methocel K-100M Premium), 0.2025 kg of colloidal silicon dioxide (CAB-O-SIL) are delumped by passing the compounds through a 20
mesh screen and then mixed in a suitable blender for 20 minutes.  0.2025 kg of magnesium stearate is screened and added to the drug mixture and blended for an additional 5 minutes.  After all the ingredients are blended together, the mixture is
compressed into tablets using a rotary press fitted with 11/32'' round standard concave punches.  The target hardness is about 13 kp.


 The tablets are then coated with a controlled release coating as follows:


 (b) Controlled Release Coating


 0.6271 kg of methacrylic acid copolymer (Eudragit S 100), 1.881 kg of zein NF (regular Grade F4000), 0.2090 kg acetyltributyl citrate, NF and 2.508 kg of talc USP are dispersed in 23.72 kg of isopropyl alcohol USP and 4.230 kg of purified water
(USP) while stirring with a homogenizer 1.664 kg of isopropyl alcohol, USP was used to rinse the homogenizer and added to the dispersion.  The coating suspension is then sprayed onto the tablets in a pan coater employing the following conditions: product
temperature of 25-35.degree.  C.; atomization pressure of approximately 25-55 psi; and a spray rate of 40-100 m/min.


 Once the controlled release coating suspension has been applied to the lot of core tablets, the controlled release coated tablets are dried on drying trays in an oven at 60.+-.5.degree.  C. for 16 hours to allow for curing of the coating.  Once
the controlled release coated tablets are cured an immediate release methylphenidate HCl coating is applied to the controlled release coated tablets as follows:


 (c) Immediate Release Coat


 1.830 kg of methylphenidate hydrochloride, 1.826 kg of hydroxypropyl methylcellulose (Methocel.RTM.  E5 Premium) and 0.0041 kg of fumaric acid NF are dissolved in 42.088 kg of purified water USP.  1.895 kg of Opadry.RTM.  II Red 85F15266 is
dispersed into 10.171 kg of water and mixed for 1 hour.  The drug solution is sprayed onto the controlled release tablets using a pan coater employing the following conditions: product temperature of 35-55.degree.  C.; atomization pressure of
approximately 25-55 psi; and a spray rate of 50-150 ml/min. The tablets were further film and polish coated then weighed.  The final tablets have approximately 13.5 mg of methylphenidate HCl in the immediate release coating and approximately 40.5 mg of
methylphenidate HCl in the core.


 The dissolution profile for the formulations in Example 4 was conducted with USP apparatus No 1, at 100 rpm, N=12 and pH 7.5 phosphate buffer at intervals over 10 hours, depicted in the graph of FIG. 6 and TABLE 5 as follows:


 TABLE-US-00006 TABLE 5 % Time dissolved 0.5 hour 24% 1 hour 24% 2 hours 30% 4 hours 53% 8 hours 90% 10 hours 100%


 The resulting tablets for the formulations in Example 4 were tested in human subjects along with CONCERTA.TM.  brand methylphenidate HCl tablets.  Subjects were given either a single dose of 54 mg of methylphenidate controlled release
formulation described herein or an equivalent amount in a single dose of CONCERTA.TM.  brand sustained release methylphenidate HCl tablet under fasting and non-fasting conditions.  The results of the in vivo testing are provided in TABLE 6 and TABLE 7
representing fasting and non-fasting conditions, respectively.


 TABLE-US-00007 TABLE 6 (FASTING) N = 28 Methylphenidate % Lower Upper controlled release Concerta .TM.  Ratio Limit, Limit C.sub.max 14.92 15.49 96.30 90.79, 102.15 AUC.sub.inf 142.16 143.58 99.01 95.73, 102.17 T.sub.max2 7.10 6.01 118.13


 TABLE-US-00008 TABLE 7 (NON-FASTING) N = 23 Methylphenidate % Lower Upper controlled release Concerta .TM.  Ratio Limit, Limit C.sub.max 13.69 14.37 95.30 88.83, 102.24 AUC.sub.inf 145.32 153.22 94.84 91.95, 97.83 T.sub.max2 9.01 6.32 142.57


 While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skilled in the art.  Accordingly, this
specification is intended to cover all embodiments of the invention and modifications thereof which do not depart from the spirit and scope of the invention.


* * * * *























				
DOCUMENT INFO
Description: 1. Field of the Invention The present invention relates to the improved dosing of medication. Specifically, this invention improves the therapeutic effect of a central nervous system stimulant such as methylphenidate hydrochloride by delivering the medication over apredetermined period of time. In the present invention an initial immediate dose of the central nervous system stimulant is delivered followed by a second controlled dose of the medication from a single oral dosage form. The invention helps improvepatient compliance and decreases the need for additional daily doses of the medication. 2. Description of the Related Art Methylphenidate is a central nervous system stimulant used to treat Attention-Deficit Disorder (ADD) and Attention-Deficit Hyperactivity Disorder (ADHD), available commercially as, e.g. RITALIN SR.RTM., CONCERTA.TM., METADATE.TM. CD capsulesand METEADATE.TM. ER Tablets. The beneficial results seen by clinicians in the treatment of ADD and ADHD has resulted in widespread use of methylphenidate in more than two million patients annually. Methylphenidate exists in four separate opticalisomers, 1-threo, d-erythro, d-threo and 1-erythro, with the threo pair of enantiomers (racemate) of methylphenidate hydrochloride generally administered for the treatment of ADD and ADHD. Methylphenidate hydrochloride is a mild central nervous systemstimulant with pharmacological properties similar to that of amphetamines. The side effects which are associated with the use of methylphenidate include anorexia, weight loss, insomnia, dizziness and dysphoria. Methylphenidate is categorized by the DEAas a Schedule II controlled substance because it produces a euphoric effect when administered intravenously or through inhalation or ingestion, and thus carries a high potential for abuse. Numerous sustained release formulations of methylphenidate which provide for a slow release of the medication over a predetermined period of time have been developed and so